1. Field of the Invention
The present invention relates to the measurement of the concentration of substances, and particularly but not exclusively to the measurement of the concentration of substances such as oxygen, for example, in human or animal tissue.
2. Description of Related Art
The survival of tissue cells relies on an adequate supply of oxygen to the mitochondria within the tissue cells. Over recent years, several technologies have been developed for monitoring oxygenation at the different stages of oxygen transport from the outside environment to tissue cells. Most importantly, the measurement of oxygen partial pressure in tissue (PtiO2) has provided a measure of oxygen availability at the cellular level.
Polarographic (redox based) electrodes have been widely used for monitoring tissue oxygen but a number of disadvantages remain unresolved. The fundamental problem at low oxygen pressures is that the electrodes consume a significant quantity of oxygen by the electro-chemical reduction reaction. As a result, the electrode tends to underestimate the level of tissue oxygen—an effect which is most evident under conditions of tissue hypoxia. Other reported problems concern long-term stability and measurement drift. Routine calibration is required to compensate for drift and the calibration procedure itself is frequently a complex and time-consuming process.
Recently, tissue oxygen sensors based on new-generation optical technology for continuous quantitative monitoring of regional pO2 in tissue and fluids have been developed. These oxygen sensors are based on the property of certain chemical compounds (luminophores) to produce an ‘afterglow’ or ‘luminescence’ when they are illuminated and stimulated with a short burst of light. The duration of this luminescence signal is related to the amount of oxygen present in the vicinity of the luminophor dye compound and typically lasts for only a few millionths of a second but nevertheless is long enough to be able to detect it reliably using modern optoelectronic devices.
Typically, short pulses of (e.g. green or blue) light are transmitted along a fibre to excite a luminophor situated at the fibre tip. The luminophor is usually immobilised within a polymer matrix or solgel. Following excitation, the resulting emission of the (longer wavelength) luminescent light, quenched by the presence of oxygen molecules, travels back up the fibre and is detected by an appropriate instrument. The decay lifetime of the luminescence (typically microseconds) is inversely proportional to the concentration of dissolved oxygen, and is electronically processed to provide an absolute value for pO2 in mm Hg, kPa or Torr.
Luminescence lifetime is longest at low oxygen partial pressures making such sensors very sensitive in the physiological range 0-150 mmHg. This makes them particularly suited to measuring regions of hypoxia in tissue; in contrast to all other types of sensor. Since luminescence-based sensors do not show significant oxygen consumption, these sensors can not only be used to gain spatial pO2 information, but can be left in situ for monitoring the long-term, temporal evolution in tissue pO2. Additionally, when such systems are based on luminescence lifetime rather than luminescence intensity, they are much less prone to artefacts (e.g. due to variation in the intensity of the light source, ambient lighting, photo-bleaching etc.).
A discussion of fibre optic chemical sensors may be found in “Fibre-Optic Chemical Sensors and Biosensors” by Otto S. Wolfbeis, Anal. Chem. 2004, 76, 3269-3284, the contents of which are incorporated herein by way of reference.
The difficulties of developing a practical fibre-optic oxygen sensor for clinical application are considerable. Optical-fibre-only oxygen sensors based on a simple, bare, fibre-optic construction are largely unsuitable for human in-vivo (e.g. clinical) application—because they are fragile, difficult to insert and in a single-fault condition may expose the patient to unacceptable risks. These include the risk of broken optical fibre (silica) entering the blood stream as a result of breaking in situ and/or the risk of the sensing tip becoming detached from the sensor and itself entering the blood stream or implanting in tissue.
One arrangement for measuring the concentration of oxygen is disclosed in U.S. Pat. No. 6,531,097, which is incorporated herein by way of reference. A sensor comprises an optical fibre. At one end of the fibre, the buffer layer is stripped away to leave the fibre and its cladding. The end of the fibre is coated with a body of moulded polymer in which are disposed silica particles containing a fluorescent dye such as tris4,7-diphenyl-1,10-phenanthroline)Ru(II)Cl. That body and the remainder of the fibre and its cladding, up to the buffer layer, are provided with a protective coating of the same polymer, without the silica gel particles. In one embodiment, a rigid needle of metal or ceramic is provided over the fibre and its cladding back to the buffer layer, and is also sealed to the buffer layer. This is said to improve robustness. In the embodiment described and illustrated, the end of the fibre and its dye containing body and protective polymer coating are exposed. It is said that the end of the fibre may be enclosed within the bore of the needle, although no further details are given.
A potential problem associated with known fibre-optic sensors, including that in U.S. Pat. No. 6,531,097, is that the measurement site is at the very tip (or distal end) of the fibre, which is also in the region at which maximal tissue trauma occurs (due to mechanical insertion) as well as being the region at which the tissue is most occluded (due to mechanical compression). These effects can combine to cause undesirable measurement artefacts. In addition, in most types of tissue, oxygen values can vary markedly from one micro region to the next. As a result the measurement can be very sensitive to the precise positioning of the tip, and to movements which may alter that positioning, including breathing, blood flow and so forth. Readings may fluctuate even when a patient is kept as stationary as possible.